Identification of naturally processed CD8 T cell epitopes from prostein, a prostate tissue‐specific vaccine candidate

Abstract

Prostein is a prostate tissue-specific protein that is uniquely and abundantly expressed in normal and cancerous prostate tissues. Due to this expression profile, we examined the immunogenicity of prostein as a potential vaccine candidate for prostate cancer. To determine the presence of CD8 T cells specific for naturally processed prostein-derived epitopes in healthy individuals, we developed and applied an in vitro stimulation protocol. Using this protocol, we identified CD8 T cells specific for prostein in the peripheral blood of a male and a female donor. Prostein-specific CD8 T cell clones specifically recognized prosteinexpressing targets, including prostate tumor cell lines expressing the relevant HLA alleles. CD8 T cell clones isolated from the male donor were significantly less effective in recognizing target cells compared to cells isolated from the female donor and appeared to recognize subdominant epitopes. The identification of a prostein-specific CD8 T cell repertoire supports the development of prostein in vaccination strategies against prostate cancer. Furthermore, the naturally processed peptide epitopes identified provide tools for the development of peptide-based vaccination strategies against prostate cancer and for monitoring of prostein-specific responses in vaccinated patients.

PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8+ T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination

“…This finding is important because SDDs are capable of conferring protective immunity in certain conditions (54, 55). They are ‘less visible’ to the immune system and may thus escape central or peripheral tolerance mechanisms in mice (56, 57) and humans (58). …”

Modification of a Tumor Antigen Determinant To Improve Peptide/MHC Stability Is Associated with Increased Immunogenicity and Cross-Priming a Larger Fraction of CD8+ T Cells

“…However, T cells targeting subdominant determinants, which induce fewer responder T cells, can also play a role in the control of tumors (1, 2) and virus infections (3–5). Limited immunological tolerance toward subdominant determinants found in self tumor associated antigens in mice (6–8) and in humans (9) makes them attractive targets for CD8+ T cell-based immunotherapy approaches. Understanding the mechanisms contributing to the subdominant phenotype may facilitate inclusion of T cells targeting a broader repertoire of determinants for vaccination and immunotherapy.…”

T Cell-Based Gene Therapy of Cancer

“…Because of the impact of central tolerance on the T cell repertoire to self-antigens, tumor antigen-specific T cells isolated from cancer patients or from healthy volunteers typically are of low affinity. 42 An alternative approach involves the engineering of high-affinity TCR by directed evolution of isolated tumor antigen-specific TCRα/β chains using any one of a number of elegant genetic approaches, such as phage display libraries, or alternatively by strategies to enhance avidity by improving the steric behavior of the TCR. 42 An alternative approach involves the engineering of high-affinity TCR by directed evolution of isolated tumor antigen-specific TCRα/β chains using any one of a number of elegant genetic approaches, such as phage display libraries, or alternatively by strategies to enhance avidity by improving the steric behavior of the TCR.…”

“…Attempts to overcome this issue have included the isolation of T cells in a xenogeneic setting (e.g., vaccination of mice transgenic for human leukocyte antigen-A2) 4 or allogeneic setting (during graft versus host disease (GVHD)), 41 or by generating T cells to genderrestricted antigens (such as prostate or ovary) from peripheral blood cells of the opposite gender. [42][43][44][45][46] Naturally, such efforts must be carefully controlled to ensure retained specificity for the target antigen, 47 and could theoretically introduce neoepitopes that could be targeted by the recipient's immune system, leading to rejection of the infused product. [42][43][44][45][46] Naturally, such efforts must be carefully controlled to ensure retained specificity for the target antigen, 47 and could theoretically introduce neoepitopes that could be targeted by the recipient's immune system, leading to rejection of the infused product.…”